During this period, we have utilized our large cohort of patients with CVI and a closely related disease, selective IgA deficiency to conduct two clinical studies. Project 1: Studies of Patients with Common Variable Immunodeficiency and IgA Deficiency Protocol 01-I-0153: The Immunologic Basis of GI Disease in CVI. Patients with CVI not infrequently develop a syndrome of weight loss, malabsorption, and villous atrophy probably due to T cell-mediated autoimmunity to mucosal cells. In some cases, this can be severe enough to lead to uncontrollable weight loss and death. In this study we are defining the gastrointestinal function in patients with and without GI disease focusing on cells obtained by mucosal biopsies. Our aim is to determine if the GI pathology is due to a Th1-mediated inflammation that would therefore be amenable to anti-TNF therapy of some sort. We have completed studies of several CVI patients and have shown that one symptomatic patient does in fact have evidence of a Th1-mediated inflammation in the intestinal lamina propria. Protocol 02-C-0009: A trial of BlyS in the treatment of IgA deficiency. BlyS is a TNF-R family member that has been shown to stimulate B cell Ig production. In collaboration with Human Genome Sciences, the developer of this molecule, and Dr. David Nelson of the National Cancer Institute, the PI of this study, we are conducting a sole site phase I study of the toxicity of this agent in patients with IgA deficiency. To accomplish this task we are drawing on the large cohort of patients with IgA deficiency that we follow on an on-going basis. So far we have enrolled 10 of the 15 patients slated for this study. Project 2: Studies of the Hyper-IgM Syndrome: T Cell Abnormalities in HIGM1 The hyper-IgM syndrome consists of at least four distinct entities each due to a separate molecular defect. The most common form is X-linked hyper-IgM syndrome (HIGM1) and is due to an X-linked mutation in the gene encoding CD40 ligand. As a result patient B cells do not undergo class switching and exhibit normal or elevated IgM levels and reduced IgG and IgA levels. In a broad study of the immunological consequences of this defect focusing on T cell function, we showed that patient T cells stimulated with the polyclonal activator, anti-CD3, were poor inducers of APC IL-12 production, and, as a consequence, produced greatly reduced amounts of IFN-gamma. That this was due to the fact that the T cells did not express CD40L was shown by the fact that patient APC's produced normal amounts of IL-12 when subjected to stimulation with LPS or SAC and by the fact that addition of rCD40-trimer to the T cell culture restored IFN-gamma production. An additional abnormality consisted of the fact that patient CD4 and CD8 cells fail to mature into memory cells, presumably because CD40L signaling is necessary to stimulate the APC to provide co-stimulation. The significance of these studies lies in the demonstration that they show that the molecular defect in HIGM1 also leads to T cell defects that explain the fact that HIGM1 patients are subject to opportunistic infections. As a result of the above study, it occurred to us that treatment of patients with rCD40L-trimer might greatly improve their T cell function and therefore have a major effect on the course of their disease. Accordingly, with the collaboration of the Immunex Corp. as a source of rCD40L-trimer, we instituted a clinical study of rCD40L-trimer adminstered to patients by a subcutaneous route. The results of this trial are more fully described in the write up of Dr. Ashish Jain who began this study while a fellow in the Mucosal Immunity Section, and is now a tenure-track investigator conducting independent research. Suffice to say here that such treatment resulted in tangible improvements in T cell function and lymph node architecture and thus holds promise as a therapy for patients.